This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We request allocation on Anton for extended MD simulations that will investigate several membrane transporters representing major energy-coupling mechanisms of transport in living cells. The proposed studies will characterize the nature and magnitude of protein conformational changes induced by binding/unbinding of the substrate and the driving energy-coupling events on a microsecond time scale, and reveal structurally unknown states of the transporters. The results will bring an unprecedented time scale to the dynamical description of these slow molecular machines for the first time, and given the experimental inaccessibility of such information, will revolutionize our mechanistic view of their function.